Earlier, we filed and issued two related patents on 7-des-proline-vasopressin antagonists, U.S. Pat. Nos. 4,481,193 and 4,481,194, both filed on Mar. 7, 1984 and issued on Nov. 6, 1984.
Recently, one of us filed another patent application, U.S. Ser. No. 747,640, covering potent vasopressin antagonists whose structures are distinguished by having two arginine-like units in the side chain which may be, in turn, optionally N-methylated. The present invention was conceived and reduced to practice earlier.
Peptide chemists recognize that N-methylamino acid units in a peptide chain exert a conformational effect on the preceding amino acid unit. Whether this unnatural positioning will exert an influence on biological activity is unpredictable.
The compounds disclosed in this application have been found to retain potent vasopressin antagonist activity, in fact, to have enhanced activity when compared with their des-N-methyl congeners.
In the description herein and in the claims, the nomenclature common in the art of peptide and vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form. In certain structural formulas, the thio members of the Pmp and Cys units are added for clarity.
Certain of the peptide art designations used herein are the following: Pmp, .beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid; Tmp, .beta.-mercapto-.beta.,.beta.-cyclotetramethylenepropionic acid; Tyr(Alk), O-alkyltyrosine; Abu, .alpha.-amino-n-butyric acid; Gly, glycine; Tyr, tyrosine; Phe, phenylalanine; Phe(Alk), 4-alkylphenylalanine, Val, valine; Ile, isoleucine; MeArg, N-methylarginine; Asn, asparagine; Tos, tosylate; BHA, benzhydrylamine; DMAP, 4-dimethylaminopyridine; DIEA, diisopropylethylamine; HF, hydrogen fluoride; 4-MeBzl, 4-methylbenzyl; TFA, trifluoroacetic acid; DCC, dicyclohexylcarbodiimide; Boc, t-butyloxycarbonyl; Z, benzyloxycarbonyl; VSP, vasopressin; HBT, hydroxybenzotriazole; ACM, acetamidomethyl.
In the definitions such as MeArg above, Me denotes a methyl located on the amido nitrogen of the peptide unit concerned.
"Alk" represents a lower alkyl of 1-4 carbons. For example, these may be optionally attached to the oxygen substituent of a tyrosine unit at position 2, especially at the 4'-position of the tyrosine unit, at the 4'-position of the phenylalanine unit at position 2 or at the terminal amido nitrogen (A) of the tail. Such alkyl substituents include methyl, ethyl, n-propyl, isopropyl or butyl. In the 2-tyrosine or 2-phenylalanine units, ethyl is preferred.